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Published on: July 13, 2014
Alcohol's Dysregulation of Maternal-Fetal IL-6 and p-STAT3 Is a Function of Maternal Iron Status
Nipun Saini1, Kaylee K Helfrich1, Sze Ting Cecilia Kwan1
1Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, North Carolina.
Insights
Prenatal alcohol exposure (PAE) disrupts iron regulation by activating the IL-6/JAK2/STAT3 pathway. A prenatal iron-fortified (IF) diet normalizes these changes, suggesting IF as a potential therapy for PAE-related deficits.
Area of Science:
- Biochemistry
- Developmental Biology
- Toxicology
Background:
- Prenatal alcohol exposure (PAE) leads to growth and neurodevelopmental issues, exacerbated by maternal iron deficiency (ID).
- PAE induces fetal anemia, brain ID, and elevated hepatic iron through increased hepcidin synthesis.
- A prenatal iron-fortified (IF) diet can normalize these PAE-induced changes.
Purpose of the Study:
- To investigate how iron status and PAE affect the EPO/BMP6/SMAD and IL-6/JAK2/STAT3 pathways governing hepcidin production.
- To determine the efficacy of an iron-fortified diet in mitigating PAE-induced hepcidin dysregulation.
Main Methods:
- Pregnant rats were fed iron-deficient (ID), iron-sufficient (IS), or iron-fortified (IF) diets.
- Alcohol or maltodextrin was administered daily during late gestation (GD 13.5-19.5).
- Hepatic protein and gene expression, including hepcidin regulators, were analyzed at GD 20.5.
Main Results:
- PAE reduced SMAD signaling but increased IL-6 expression and STAT3 activation in maternal and fetal liver.
- Fetal cytokine responses to PAE were less pronounced than in dams.
- Dietary iron fortification significantly reduced IL-6 expression and normalized STAT3 activation in response to PAE.
Conclusions:
- Alcohol-induced hepcidin elevation in PAE is mediated by the IL-6/JAK2/STAT3 pathway.
- Iron fortification normalizes these signaling pathways, suggesting it counteracts alcohol's effects on hepcidin.
- Prenatal iron fortification shows promise as a therapeutic strategy for PAE.
Background:
Prenatal alcohol exposure (PAE) causes long-term growth and neurodevelopmental deficits that are worsened by maternal iron deficiency (ID). In our preclinical rat model, PAE causes fetal anemia, brain ID, and elevated hepatic iron via increased maternal and fetal hepcidin synthesis. These changes are normalized by a prenatal iron-fortified (IF) diet. Here, we hypothesize that iron status and PAE dysregulate the major upstream pathways that govern hepcidin production-EPO/BMP6/SMAD and IL-6/JAK2/STAT3.
Methods:
Pregnant, Long Evans rat dams consumed ID (2 to 6 ppm iron), iron-sufficient (IS, 100 ppm iron), or IF (500 ppm iron) diets and received alcohol (5 g/kg) or isocaloric maltodextrin daily from gestational days (GD) 13.5 to 19.5. Protein and gene expression were quantified in the 6 experimental groups at GD 20.5.
Results:
PAE did not affect Epo or Bmp6 expression, but reduced p-SMAD1/5/8/SMAD1/5/8 protein ratios in both IS and ID maternal and fetal liver (all p's < 0.01). In contrast, PAE stimulated maternal hepatic expression of Il-6 (p = 0.03) and elevated p-STAT3/STAT3 protein ratios in both IS and ID maternal and fetal liver (all p's < 0.02). PAE modestly elevated maternal Il-1β, Tnf-α, and Ifn-γ. Fetal cytokine responses to PAE were muted compared with dams, and PAE did not affect hepatic Il-6 (p = 0.78) in IS and ID fetuses. Dietary iron fortification sharply attenuated Il-6 expression in response to PAE, with IF driving a 150-fold decrease (p < 0.001) in maternal liver and a 10-fold decrease (p < 0.01) in fetal liver. The IF diet also normalized p-STAT3/STAT3 ratios in both maternal and fetal liver.
Conclusions:
These findings suggest that alcohol-driven stimulation of the IL-6/JAK2/STAT3 pathway mediates the elevated hepcidin observed in the PAE dam and fetus. Normalization of these signals by IF suggests that dysregulated hepcidin is driven by alcohol's disruption of the IL-6/JAK2/STAT3 pathway. Prenatal dietary IF represents a potential therapeutic approach for PAE that warrants further investigation.
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